ID C1TC_DROME Reviewed; 968 AA. AC O96553; A4V2N7; A4V2N9; Q5BIE6; Q8T0P2; DT 19-SEP-2003, integrated into UniProtKB/Swiss-Prot. DT 19-JUL-2004, sequence version 4. DT 24-JAN-2024, entry version 171. DE RecName: Full=C-1-tetrahydrofolate synthase, cytoplasmic; DE Short=C1-THF synthase; DE Includes: DE RecName: Full=Methylenetetrahydrofolate dehydrogenase; DE EC=1.5.1.5; DE Includes: DE RecName: Full=Methenyltetrahydrofolate cyclohydrolase; DE EC=3.5.4.9; DE Includes: DE RecName: Full=Formyltetrahydrofolate synthetase; DE EC=6.3.4.3; GN Name=pug; ORFNames=CG4067; OS Drosophila melanogaster (Fruit fly). OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota; OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea; OC Drosophilidae; Drosophila; Sophophora. OX NCBI_TaxID=7227; RN [1] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY. RX PubMed=9832531; DOI=10.1093/genetics/150.4.1551; RA Rong Y.S., Golic K.G.; RT "Dominant defects in Drosophila eye pigmentation resulting from a RT euchromatin-heterochromatin fusion gene."; RL Genetics 150:1551-1566(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=Berkeley {ECO:0000269|PubMed:10731132}; RX PubMed=10731132; DOI=10.1126/science.287.5461.2185; RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D., RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F., RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N., RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C., RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C., RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A., RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A., RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V., RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J., RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E., RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B., RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I., RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C., RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S., RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M., RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M., RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D., RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F., RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D., RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A., RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C., RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C., RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L., RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R., RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V., RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F., RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J., RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R., RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y., RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T., RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S., RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W., RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M., RA Venter J.C.; RT "The genome sequence of Drosophila melanogaster."; RL Science 287:2185-2195(2000). RN [3] RP GENOME REANNOTATION, AND ALTERNATIVE SPLICING. RC STRAIN=Berkeley; RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083; RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S., RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E., RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P., RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A., RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M., RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.; RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic RT review."; RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A). RC STRAIN=Berkeley; TISSUE=Embryo; RA Stapleton M., Carlson J.W., Chavez C., Frise E., George R.A., Pacleb J.M., RA Park S., Wan K.H., Yu C., Rubin G.M., Celniker S.E.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [5] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 604-968. RC STRAIN=Berkeley {ECO:0000269|PubMed:12537569}; RC TISSUE=Head {ECO:0000269|PubMed:12537569}; RX PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080; RA Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A., RA Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M., RA Celniker S.E.; RT "A Drosophila full-length cDNA resource."; RL Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002). CC -!- CATALYTIC ACTIVITY: CC Reaction=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NADP(+) = (6R)- CC 5,10-methenyltetrahydrofolate + NADPH; Xref=Rhea:RHEA:22812, CC ChEBI:CHEBI:15636, ChEBI:CHEBI:57455, ChEBI:CHEBI:57783, CC ChEBI:CHEBI:58349; EC=1.5.1.5; CC Evidence={ECO:0000250|UniProtKB:P11586}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(6R)-5,10-methenyltetrahydrofolate + H2O = (6R)-10- CC formyltetrahydrofolate + H(+); Xref=Rhea:RHEA:23700, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57455, CC ChEBI:CHEBI:195366; EC=3.5.4.9; CC Evidence={ECO:0000250|UniProtKB:P11586}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(6S)-5,6,7,8-tetrahydrofolate + ATP + formate = (6R)-10- CC formyltetrahydrofolate + ADP + phosphate; Xref=Rhea:RHEA:20221, CC ChEBI:CHEBI:15740, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, CC ChEBI:CHEBI:57453, ChEBI:CHEBI:195366, ChEBI:CHEBI:456216; CC EC=6.3.4.3; Evidence={ECO:0000250|UniProtKB:P11586}; CC -!- PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion. CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P11586}. CC -!- SUBCELLULAR LOCATION: Cytoplasm. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=B; Synonyms=D; CC IsoId=O96553-1; Sequence=Displayed; CC Name=A; Synonyms=C; CC IsoId=O96553-2; Sequence=VSP_010883; CC -!- TISSUE SPECIFICITY: Present in all tissues. CC {ECO:0000269|PubMed:9832531}. CC -!- DOMAIN: This trifunctional enzyme consists of two major domains: a N- CC terminal part, containing the methylene-THF dehydrogenase and the CC methenyl-THF cyclohydrolase activities and a larger formyl-THF CC synthetase domain. CC -!- SIMILARITY: In the N-terminal section; belongs to the tetrahydrofolate CC dehydrogenase/cyclohydrolase family. {ECO:0000305}. CC -!- SIMILARITY: In the C-terminal section; belongs to the CC formate--tetrahydrofolate ligase family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAL39291.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF082097; AAC78847.1; -; Genomic_DNA. DR EMBL; AE014297; AAG22140.2; -; Genomic_DNA. DR EMBL; AE014297; AAN13478.1; -; Genomic_DNA. DR EMBL; AE014297; AAN13479.1; -; Genomic_DNA. DR EMBL; AE014297; AAX52944.1; -; Genomic_DNA. DR EMBL; BT021278; AAX33426.1; -; mRNA. DR EMBL; AY069146; AAL39291.1; ALT_INIT; mRNA. DR RefSeq; NP_001014614.1; NM_001014614.2. [O96553-1] DR RefSeq; NP_477254.1; NM_057906.4. [O96553-2] DR RefSeq; NP_731489.2; NM_169350.3. [O96553-1] DR RefSeq; NP_731490.1; NM_169351.2. [O96553-2] DR AlphaFoldDB; O96553; -. DR SMR; O96553; -. DR BioGRID; 66423; 2. DR IntAct; O96553; 4. DR STRING; 7227.FBpp0081741; -. DR PaxDb; 7227-FBpp0081741; -. DR DNASU; 41279; -. DR EnsemblMetazoa; FBtr0082264; FBpp0081741; FBgn0020385. [O96553-1] DR EnsemblMetazoa; FBtr0082265; FBpp0081742; FBgn0020385. [O96553-2] DR EnsemblMetazoa; FBtr0082266; FBpp0081743; FBgn0020385. [O96553-2] DR EnsemblMetazoa; FBtr0100144; FBpp0099494; FBgn0020385. [O96553-1] DR GeneID; 41279; -. DR KEGG; dme:Dmel_CG4067; -. DR UCSC; CG4067-RA; d. melanogaster. [O96553-1] DR AGR; FB:FBgn0020385; -. DR CTD; 41279; -. DR FlyBase; FBgn0020385; pug. DR VEuPathDB; VectorBase:FBgn0020385; -. DR eggNOG; KOG4230; Eukaryota. DR GeneTree; ENSGT00940000167165; -. DR InParanoid; O96553; -. DR OMA; QPIMFRR; -. DR OrthoDB; 651667at2759; -. DR PhylomeDB; O96553; -. DR Reactome; R-DME-196757; Metabolism of folate and pterines. DR SignaLink; O96553; -. DR UniPathway; UPA00193; -. DR BioGRID-ORCS; 41279; 0 hits in 3 CRISPR screens. DR GenomeRNAi; 41279; -. DR PRO; PR:O96553; -. DR Proteomes; UP000000803; Chromosome 3R. DR Bgee; FBgn0020385; Expressed in head capsule and 34 other cell types or tissues. DR ExpressionAtlas; O96553; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IBA:GO_Central. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0004329; F:formate-tetrahydrofolate ligase activity; NAS:UniProtKB. DR GO; GO:0004477; F:methenyltetrahydrofolate cyclohydrolase activity; IBA:GO_Central. DR GO; GO:0004488; F:methylenetetrahydrofolate dehydrogenase (NADP+) activity; IBA:GO_Central. DR GO; GO:0008652; P:amino acid biosynthetic process; NAS:UniProtKB. DR GO; GO:0000105; P:histidine biosynthetic process; IEA:UniProtKB-KW. DR GO; GO:0009086; P:methionine biosynthetic process; IEA:UniProtKB-KW. DR GO; GO:0006164; P:purine nucleotide biosynthetic process; IEA:UniProtKB-KW. DR GO; GO:0035999; P:tetrahydrofolate interconversion; IBA:GO_Central. DR CDD; cd00477; FTHFS; 1. DR CDD; cd01080; NAD_bind_m-THF_DH_Cyclohyd; 1. DR Gene3D; 1.10.8.770; -; 1. DR Gene3D; 3.10.410.10; Formyltetrahydrofolate synthetase, domain 3; 1. DR Gene3D; 3.40.50.10860; Leucine Dehydrogenase, chain A, domain 1; 1. DR Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2. DR HAMAP; MF_01543; FTHFS; 1. DR HAMAP; MF_01576; THF_DHG_CYH; 1. DR InterPro; IPR046346; Aminoacid_DH-like_N_sf. DR InterPro; IPR000559; Formate_THF_ligase. DR InterPro; IPR020628; Formate_THF_ligase_CS. DR InterPro; IPR036291; NAD(P)-bd_dom_sf. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR000672; THF_DH/CycHdrlase. DR InterPro; IPR020630; THF_DH/CycHdrlase_cat_dom. DR InterPro; IPR020867; THF_DH/CycHdrlase_CS. DR InterPro; IPR020631; THF_DH/CycHdrlase_NAD-bd_dom. DR PANTHER; PTHR48099:SF5; C-1-TETRAHYDROFOLATE SYNTHASE, CYTOPLASMIC; 1. DR PANTHER; PTHR48099; C-1-TETRAHYDROFOLATE SYNTHASE, CYTOPLASMIC-RELATED; 1. DR Pfam; PF01268; FTHFS; 1. DR Pfam; PF00763; THF_DHG_CYH; 1. DR Pfam; PF02882; THF_DHG_CYH_C; 1. DR PRINTS; PR00085; THFDHDRGNASE. DR SUPFAM; SSF53223; Aminoacid dehydrogenase-like, N-terminal domain; 1. DR SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS00721; FTHFS_1; 1. DR PROSITE; PS00722; FTHFS_2; 1. DR PROSITE; PS00766; THF_DHG_CYH_1; 1. DR PROSITE; PS00767; THF_DHG_CYH_2; 1. DR Genevisible; O96553; DM. PE 2: Evidence at transcript level; KW Alternative splicing; Amino-acid biosynthesis; ATP-binding; Cytoplasm; KW Histidine biosynthesis; Hydrolase; Ligase; Methionine biosynthesis; KW Multifunctional enzyme; NADP; Nucleotide-binding; One-carbon metabolism; KW Oxidoreductase; Purine biosynthesis; Reference proteome. FT CHAIN 1..968 FT /note="C-1-tetrahydrofolate synthase, cytoplasmic" FT /id="PRO_0000199324" FT REGION 1..338 FT /note="Methylenetetrahydrofolate dehydrogenase and FT cyclohydrolase" FT REGION 339..968 FT /note="Formyltetrahydrofolate synthetase" FT BINDING 86..90 FT /ligand="substrate" FT /evidence="ECO:0000250" FT BINDING 133..135 FT /ligand="substrate" FT /evidence="ECO:0000250" FT BINDING 205..207 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250" FT BINDING 230 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250" FT BINDING 305..309 FT /ligand="substrate" FT /evidence="ECO:0000250" FT BINDING 413..420 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250" FT VAR_SEQ 1..34 FT /note="Missing (in isoform A)" FT /evidence="ECO:0000303|Ref.4" FT /id="VSP_010883" FT CONFLICT 879 FT /note="E -> K (in Ref. 4; AAX33426)" FT /evidence="ECO:0000305" SQ SEQUENCE 968 AA; 103504 MW; D65EC8455DD8AF2C CRC64; MSAQYQRFLK VLEKWPAEKS KVGSGEWTAE PAIKMSGAKI ISGTAVAKSI REELRNEVTA MSKQLADFVP GLRIVQVGGR EDSNVYIRMK IKAATEIGID AAHVQLPRSI TEVELLDKIN DLNEDPRVHG IIVQMPLDCD TPIDSHRITD AVSPEKDVDG LHTVNEGRLA IGDLGGFLPC TPWGCLELIR RSGVEIAGAR AVVLGRSKIV GTPAAELLKW ANATVTVCHS KTRNLEEITR SADILVVGIG VAEMVKGSWI KPGAVVIDCG INVKPDASKA SGSKLVGDVD YAEALQVAGH LTPVPGGVGP MTVAMLMKNT VRSAARFLER LAKSQWALQT LPLKPQRPVP SDIVIARAQK PKDIAVLAKE IGLEAREVSL YGNKKAKISL SVLERLKDKE VGHYVVVAGM TPTPLGEGKT TTLMGLVQAL GAHKLRNTMA ALRQPSQGPT FGIKGGAAGG GYAQVIPMEE FNLHLTGDIH AVSAANNLLA AQLDTRIFHE NTQKDKALYD RLVPAIKGQR KFSPIQLRRL QKLGITKTDP DTLTADEYGP FARLDIDPDT IMWERVVDIN DRYLRTITVG QSPTEKGISR ETRFSISVAS EIMAVLALSR SLEDMKQRLA DMVVAFDKRG KPVTADDLGV TGALAVLLKD ALEPNLMQSL EGTPVLVHAG PFANIAHGCN SIIADEVGLK LVGKNGFVCT EAGFGSDIGM EKFCNIKCRT SGRKPNAMVL VATVRAIKMH GGGAPVTPGA PLNKQYTEEN LELVQKGLPN LLQHIENGKA FGMPVVVSLN AHSADTPAEH ELVKKAALEA GAFAAVVSTH WADGGAGAVQ LADAVIKACE QGNQFRLLYD LELPLVDKMN KIATTMYGAG KVVLSPAAEE KVKRLTDAGF GNLPICMSKV SGSFTGDAKI KGAPKGFTLD VEDVYVSAGA GFVVAMCGEV TKMPGLPTRP AIYDIDLNTE TGEIEGLF //